Endogenous opioid peptides are known and are involved in the mediation or modulation of a variety of mammalian physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the effects that have been suggested include analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, learning and memory, mental illness, epileptic seizures and other neurological disorders, cardiovascular responses, and respiratory depression, see G. T. Shearman et al. J. Pharmacol. Exp. Ther., 243, 591–597, 1987.
The fact that the effects of endogenous and exogenous opioids are mediated by at least three different types of opioid receptors raises the possibility that highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications. Thus, if a ligand acts at a single opioid receptor type or subtype, the potential side effects mediated through other opioid receptor types can be minimized or eliminated.
The kappa opioid receptor is one of the three major opioid receptors that are found in the central nervous system and in the periphery, see Dhawan, B. N.; Cesselin, R.; Raghubir, R.; Reisine, T.; Bradley, P. B.; Portoghese, P. S.; Hamon, M. International Union of Pharmacology. XII. Classification of Opioid Receptors. Pharmacol. Rev. 1996, 48, 567–583. The precise roles of kappa receptors have not yet been established, but it appears that kappa-selective endogenous opioid peptides, such as dynorphin A, function both as neuro- and immuno-modulators.
A number of nonpeptide kappa agonists have been developed as promising potential analgesics, and some of them have found wide use as pharmacological tools in opioid research, see Jones, R. M.; Paterlini, M. G. κ-Opioid Receptors: recent advances and implications for drug design. Curr. Opin. Drug Discuss. Dev. 1998, 1, 175–182. Norbinaltorphimine (norBNI 1) a bivalent ligand shown in FIG. 3, which contains two naltrexone-derived pharmacophores, is a nonpeptide ligand that is highly selective and widely used as a kappa opioid receptor antagonist, see Portoghese, P. S.; Lipkowski, A. W.; Takemori, A. E. Bimorphinans as High Selective, Potent κ Opioid Antagonists. J. Med. Chem. 1987, 30, 238–239.
Additionally, International Patent Application PCT/US 99/18021, filed Jun. 8, 1999, reports certain kappa receptor antagonists. Data is provided for certain specific 5′-guanidinonaltrindole compounds demonstrating the compounds were found to have activity as kappa receptor antagonists.
Despite the above reports, there exists a need for kappa receptor agonists that can be used as therapeutic agents such as analgesics, or as pharmacological tools to further investigate kappa receptor binding, structure, and function. In particular, there is a need for potent and selective agonists that can be used to treat conditions associated with kappa receptor function.